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Psychedelics as anti-inflammatory agents

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Abstract

Serotonin (5-hydroxytryptamine, 5-HT)2A receptor agonists have recently emerged as promising new treatment options for a variety of disorders. The recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression, obsessive-compulsive disorder (OCD), and addiction, has ushered in a renaissance in the way these compounds are perceived in the medical community and populace at large. One emerging therapeutic area that holds significant promise is their use as anti-inflammatory agents. Activation of 5-HT2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioural levels. This review discusses the role of the 5-HT2A receptor in the inflammatory response, as well as highlight studies using the 5-HT2A agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] to treat inflammation in cellular and animal models. It also examines potential mechanisms by which 5-HT2A agonists produce their therapeutic effects. Overall, psychedelics regulate inflammatory pathways via novel mechanisms, and may represent a new and exciting treatment strategy for several inflammatory disorders.

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... Additionally, preclinical and neuroimaging research indicate a number of compelling biological mechanisms of psychedelics related to stimulation of 5-HT 2A R and downstream signaling pathways relevant to AD. These mechanisms include promotion of structural and functional neuroplasticity (Catlow et al. 2013;Lima da Cruz et al. 2018;Ly et al. 2018), post-acute changes in key signaling pathways such as brain-derived neurotrophic factor (BDNF) (Hutten et al. 2021;Ly et al. 2018), anti-inflammatory effects (Flanagan and Nichols 2018), as well as acute and post-acute changes in brain functional connectivity (Barrett et al. 2020a, b;Carhart-Harris et al. 2012;Carhart-Harris et al. 2017;Preller et al., 2020). This review provides a detailed examination of potential mechanisms of classic psychedelics as possible treatments for patients with AD and describes the rationale for targeted investigation of psychedelics in patients with early AD (e.g., ClinicalTrials.gov ...
... Preclinical studies have shown robust anti-inflammatory effects of classic psychedelics (Flanagan and Nichols 2018). The 5-HT 2A R agonist psychedelics (R)-2,4dimethoxy-4-iodoamphetamine [(R)-DOI] and LSD (among others) have been found to suppress TNF-α induced inflammation in rat aortic smooth muscle cells, with (R)-DOI exhibiting substantial potency in this regard (Yu et al. 2008). ...
... It is our contention that there may be truth to both. Neuroplasticity inducing and anti-inflammatory properties of classic psychedelics suggest the potential for purely biological therapeutic activity across several mechanisms, even at doses that would not produce strong psychoactive effects (Flanagan and Nichols 2018;Ly et al. 2018;Shao et al. 2021). Thus, low-dose psychedelic treatments could have specific applications that may not necessitate subjective effects, such as reducing brain atrophy in neurodegenerative conditions, or recent work showing persisting reductions in migraine after a single dose of psilocybin that were not associated with psychoactive effects (Schindler et al. 2021). ...
Article
Serotonin 2A receptor (5-HT2AR) agonist "classic psychedelics" are drawing increasing interest as potential mental health treatments. Recent work suggests psychedelics can exert persisting anxiolytic and antidepressant effects lasting up to several months after a single administration. Data indicate acute subjective drug effects as important psychological factors involved in observed therapeutic benefits. Additionally, animal models have shown an important role for 5-HT2AR agonists in modulating learning and memory function with relevance for Alzheimer's Disease (AD) and related dementias. A number of biological mechanisms of action are under investigation to elucidate 5-HT2AR agonists' therapeutic potential, including enhanced neuroplasticity, anti-inflammatory effects, and alterations in brain functional connectivity. These diverse lines of research are reviewed here along with a discussion of AD pathophysiology and neuropsychiatric symptoms to highlight classic psychedelics as potential novel pharmacotherapies for patients with AD. Human clinical research suggests a possible role for high-dose psychedelic administration in symptomatic treatment of depressed mood and anxiety in early-stage AD. Preclinical data indicate a potential for low- or high-dose psychedelic treatment regimens to slow or reverse brain atrophy, enhance cognitive function, and slow progression of AD. In conclusion, rationale and potential approaches for preliminary research with psychedelics in patients with AD are presented, and ramifications of this line of investigation for development of novel AD treatments are discussed.
... Within the brain, depression, addiction, Alzheimer's, and Parkinson's all appear to be linked to neuroinflammatory states (5)(6)(7). There are currently three main classes of anti-inflammatory drugs: non-steroidal anti-inflammatory drugs (NSAIDs), steroids such as prednisone, and biologics which act like sponges to "soak up" inflammatory cytokines (1). ...
... Classical psychedelics act principally on the 5hydroxytryptamine receptors (5-HTRs) to produce their psychological effects, specifically the 5-HT2a receptor (5). These same receptors are well-known to have the potential to regulate inflammation within the central nervous system and peripherally (15). ...
... This remains a fundamental research question and strong evidence exists on both sides of the debate (73). Few human trials on the therapeutic effects of psychedelics at sub-behavioral "micro-" doses have been completed, but results from animal and cell studies for their use as anti-inflammatories are promising (5). In contrast, studies on the psychological effects of micro-dosing psychedelics seem to be explained by placebo effect (74,75). ...
Article
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Objective: Stroke and traumatic brain injury (TBI) are among the leading causes of disability. Even after engaging in rehabilitation, nearly half of patients with severe TBI requiring hospitalization are left with major disability. Despite decades of investigation, pharmacologic treatment of brain injury is still a field in its infancy. Recent clinical trials have begun into the use of psychedelic therapeutics for treatment of brain injury. This brief review aims to summarize the current state of the science's relevance to neurorehabilitation, and may act as a resource for those seeking to understand the precedence for these ongoing clinical trials. Methods: Narrative mini-review of studies published related to psychedelic therapeutics and brain injury. Results: Recent in vitro, in vivo , and case report studies suggest psychedelic pharmacotherapies may influence the future of brain injury treatment through modulation of neuroinflammation, hippocampal neurogenesis, neuroplasticity, and brain complexity. Conclusions: Historical data on the safety of some of these substances could serve in effect as phase 0 and phase I studies. Further phase II trials will illuminate how these drugs may treat brain injury, particularly TBI and reperfusion injury from stroke.
... It remains unknown, how just a single administration of a psychedelic can produce such long-term therapeutic effects. An interesting theory proposed by Flanagan and Nichols suggests that this may occur due to psychedelic induced anti-inflammatory responses whereby the psychedelic reduces neuroinflammation associated with MDD, which could otherwise facilitate relapse back into a depressed state (Kyzar et al., 2017;Flanagan and Nichols, 2018). Anti-inflammatory pathways could involve activation of 5-HT 2A , Sigma-1, and TAAR receptors present in multiple cell types involved in the immunomodulation of the CNS. ...
... Traditional antidepressant drugs such as SSRIs and SNRIs are reported to lower inflammation and promote hippocampal neurogenesis (Santarelli et al., 2003;Warner-Schmidt et al., 2011;Samuels et al., 2015;Gałecki et al., 2018). Psychedelics have also been shown to reduce proinflammatory biomarker expression in several models, including in vitro, animal, and human studies (Szabo et al., 2014;Flanagan and Nichols, 2018;Flanagan et al., 2019;Nardai et al., 2020;Uthaug et al., 2020), but it remains to be investigated if this anti-inflammatory mechanism is also involved in the antidepressant effects of psychedelics to treat MDD. One of the possible mechanisms would be prevention of inflammatory-mediated tryptophan methabolism via the IDO/kynurenine pathway (Miura et al., 2008). ...
... therefore, blockade of co-stimulatory molecules an attractive immunosuppressive strategy (Kozlowska et al., 2021a). The unique properties of psychedelics in suppressing inflammatory responses (Szabo et al., 2014b;Flanagan and Nichols, 2018;Nardai et al., 2020), and promoting neural survival (Szabo et al., 2016) and plasticity (Ly et al., 2018), could be a strong rationale for the hypothesis that psychedelics might support grafted cells and facilitate their survival for therapeutic benefits. ...
Article
The studies of psychedelics, especially psychedelic tryptamines like psilocybin, are rapidly gaining interest in neuroscience research. Much of this interest stems from recent clinical studies demonstrating that they have a unique ability to improve the debilitating symptoms of major depressive disorder (MDD) long‐term after only a single treatment. Indeed, the Food and Drug Administration (FDA) has recently designated two Phase III clinical trials studying the ability of psilocybin to treat forms of MDD with "Breakthrough Therapy" status. If successful, the use of psychedelics to treat psychiatric diseases like depression would be revolutionary. As more evidence appears in the scientific literature to support their use in psychiatry to treat MDD on and substance use disorders (SUD), recent studies with rodents revealed that their therapeutic effects might extend beyond treating MDD and SUD. For example, psychedelics may have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases such as Alzheimer Disease. Preclinical work has highlighted psychedelics' ability to induce neuroplasticity and synaptogenesis, and neural progenitor cell proliferation. Psychedelics may also act as immunomodulators by reducing levels of proinflammatory biomarkers, including IL‐1β, IL‐6, Tumor Necrosis Factor‐α (TNF‐α). Their exact molecular mechanisms, and induction of cellular interactions, especially between neural and glial cells, leading to therapeutic efficacy, remain to be determined. In this review, we discuss recent findings and information on how psychedelics may act therapeutically on cells within the Central Nervous System (CNS) during brain injuries and neurodegenerative diseases.
... This practice might be especially useful for people with treatment-resistant depression. A possible mechanism of action may be anti-inflammatory [24,25]. ...
... A low socioeconomic status caused additional stress that may have hindered his progress. He described the first five years after the first psilocybin experience (20)(21)(22)(23)(24) as tentative experimentation with the methods, during which he was further re-traumatized at his studies and workplace. The five years (25)(26)(27)(28)(29) following his collapse at the workplace and subsequent unemployment, had been 'more productive', allowing him to work on his issues full-time. ...
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This article presents the case of a young man who had suffered from an early complex trauma due to daily abuse by his comprehensive school teacher and other pupils, resulting in severe anxiety and depression. He refused anti-depressive medication. Supportive psychotherapy failed to alleviate the situation, and interaction with psychiatric personnel subjectively experienced as rejections escalated his symptoms. At the age of 19 he resorted to unsupervised self-treatment with psilocybin, later augmented with a daily routine of meditation and physical exercise (yoga). Concurrently he was further re-traumatized by his social setting and workplace. After becoming unemployed at the age of 25 he dedicated himself to working with psychedelics more intensively. In his own estimation, by the age of 30 he had resolved most of his early trauma.The information for this case study was acquired in the course of semi-structured retrospective interviews 2.5 yearsapart. This case study demonstrates that concerning complex trauma, occasional high-dose psilocybin sessions alone provide insufficient treatment, and rather changes in daily routines and thought patterns are necessary. In addition, itsuggests that psychedelics could be viewed as a method for the severely depressed or anxious to experience ‘ordinary’ states of mind (e.g. calmness, hopefulness, relaxation, joy) unavailable by other means. It also suggests that living in a constantly retraumatizing environment is unlikely to allow for a full remission.
... The evidence to date suggests that classic psychedelics have immunomodulatory and anti-inflammatory properties (Flanagan and Nichols, 2018;Frecska et al., 2016;Nichols, 2009;Szabo, 2015Szabo, , 2019; carry low risk of adverse effects when administered by health professionals in a safe and supportive environment (Nutt and Carhart-Harris, 2020;Nutt et al., 2010;Rucker et al., 2018); and can be effective in the treatment of depression, anxiety and addiction (Aday et al., 2020;Carhart-Harris et al., 2016, 2018Davis et al., 2020;Goldberg et al., 2020;Johnson et al., 2014;Krebs and Johansen, 2012;Luoma et al., 2020). For example, patients with treatment-resistant depression experienced reductions in depressive symptoms after two oral doses of psilocybin. ...
... While the acute transcendent experience occasioned by classic psychedelics may presumably induce long-term changes in health behaviour that contribute to better physical health, it is plausible that there are other key mechanisms through which classic psychedelics could influence physical health, including improvements on various indices of mental health beyond the simple absence of psychological distress (e.g. increased prosociality, trait mindfulness and purpose in life; Griffiths et al., 2018;Murphy-Beiner and Soar, 2020), many of which are well-known risk factors for physical maladies (Chaddha et al., 2016;Germann, 2020;Hernandez et al., 2018); immunomodulatory and antiinflammatory effects of relevance to physical health (Flanagan and Nichols, 2018;Frecska et al., 2013Frecska et al., , 2016Szabo, 2015Szabo, , 2019Szabo et al., 2014;Thompson and Szabo, 2020;Tourino et al., 2013;Winkelman and Sessa, 2019); and high affinity to receptor subtypes (e.g. serotonin 2A receptors) that are implicated in the pathophysiology of different physical disorders (Nichols, 2009;Thompson and Szabo, 2020). ...
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Background In recent years, there has been significant research on the mental health effects of classic psychedelic use, but there is very little evidence on how classic psychedelics might influence physical health. Aims The purpose of the present study was to investigate the associations between lifetime classic psychedelic use and markers of physical health. Methods Using data from the National Survey on Drug Use and Health (2015-2018) with 171,766 (unweighted) adults aged 18 or above in the United States, the current study examined the associations between lifetime classic psychedelic use and three markers of physical health (self-reported overall health, body mass index, and heart condition and/or cancer in the past 12 months) while controlling for a range of covariates. Results Respondents who reported having tried a classic psychedelic at least once in their lifetime had significantly higher odds of greater self-reported overall health and significantly lower odds of being overweight or obese versus having a normal weight. The association between lifetime classic psychedelic use and having a heart condition and/or cancer in the past 12 months approached conventional levels of significance, with lower odds of having a heart condition and/or cancer in the past 12 months for respondents who had tried a classic psychedelic at least once. Conclusion The results of the present study suggest that classic psychedelics may be beneficial to physical health. Future research should investigate the causal effects of classic psychedelics on physical health and evaluate possible mechanisms.
... receptor mRNA over several immune-related tissues including spleen, thymus, and circulating lymphocytes [201]. There have been several studies to determine the role of 5-HT2A receptors in the human immune response and many results varied from one another, but most studies supporting the role of 5-HT2 receptor activation as proinflammatory [202]. Rodent studies with DOI assessing the immune response show a suppression of the immune response [203] by psychedelics by inhibiting ...
... Another in vitro study on mice reported dose-related suppression in B-cell proliferation, IL-2 production by TH-1, TH2 cell-derived production of IL-4, T-lymphocyte effector function and Natural Killer cell function [205]. The antiinflammatory effects of psychedelics could potentially be used for inflammatory diseases such as asthma [202] as well as autoimmune conditions [206] however controlled trials are required to assess the benefits and adverse effects. ...
Article
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Psychedelics might be the oldest psychoactive agents known used for inducing religious or mystical experiences. Their strong psychoactive effect was discovered accidentally in 1943 after the synthesis of Lysergic acid diethylamide (LSD) in 1937. These drugs became a mainstream area of research following the synthesis of LSD, however, several political and social factors led to their ban in 1966, after which research on psychedelics was limited. These drugs became a major topic of scientific and ethical debate in the 1990’s and the recent times have seen a ‘Psychedelic renaissance’ where the therapeutic value of psychedelics is being reconsidered. This article reports the historic perspective of psychedelics, pharmacologic action by 5-HT2A receptor agonism, psychological effects and compares the proposed therapeutic uses including uses in depression, PTSD, anxiety-related disorders, drug and alcohol addiction, neurodegenerative diseases and auto-immune diseases to potential harms including development of tolerance, hallucinogen persisting perception disorder and potential psychosis. An analysis of history, pharmacology, and comparison of benefits and harms lead to the conclusion that the potential therapeutic benefits significantly outweigh the potential harms thus further research and clinical trials need to be conducted across different countries and cultures for legal approval in clinical use.
... Since Sig-1R stimulation mitigates intracellular stress, regulates immune processes and protects against apoptotic cell death, one may suppose similar outcome from DMT administration in several medical conditions like stroke, general brain hypoxia, traumatic brain injury, myocardial infarct and other pathologies including IRI-s or neuroinflammation. Two recent reviews address the potential use of psychedelics (DMT included) in brain injury and inflammation [16,17]. The Sig-1R is also known to regulate morphogenesis of neuronal cells, such as neurite outgrowth, myelination, and synaptogenesis [18], therefore, neuroregeneration is reasonably expected from DMT action. ...
... Indeed, in patients with depression, the hypothalamic-pituitary-adrenal axis is deregulated, the glucocorticoid response to stress is flattened, morning cortisol concentrations are low, and glucocorticoid receptor resistance is observed. Moreover, SA history and SI have been specifically linked to decreased cortisol response to stress [109,110]. Therefore, a psilocybin-induced significant release of anti-inflammatory cortisol, corticosterone, cortisone, and 11-dehydrocorticosterone could activate an anti-inflammatory response (similar to how insulin activates insulin receptors in insulin-resistance syndrome) and could reduce the levels of pro-inflammatory cytokines, such as TNFα and IL-6 [107]. ...
Article
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The available interventions for people who are at risk of suicide have limited efficacy. Recently, research on new mental health treatments has started to consider psychedelic compounds, particularly psilocybin, a molecule with a few thousand years of history of use in human societies. The possible effects of psilocybin on suicidal ideation and behaviors have not been specifically studied yet; however, the current knowledge on the suicidal process and the available data on es/ketamine suggest that psylocibin could be used to modulate the thoughts and behavioral patterns in individu- als who are at risk of suicidal behaviors. Here, we summarize the available evidence on the possible mechanisms underlying psilocybin positive effects on suicide risk. Major pathways related to suicidal behaviors that might be modulated by psylocibin include serotonin receptors. Specifically, psylocibin directly stimulates the serotonin 2A receptor (5HT2A), targeting the inflammatory and oxidative stress pathways and leading to a rapid increase in brain plasticity and inflammation suppression and increases in cognitive flexibility, spirituality, and empathy. We also present preliminary epidemio- logical data and provide a rationale for studying psilocybin in individuals with suicidal ideation or who are at risk of suicidal behaviors. This review presents a framework to understand the basis for psilocybin use in individuals who are at risk of suicidal behaviors and calls for clinical studies.
... The primary mechanism of action of classic psychedelics is via the 5-HT 2A serotonin receptor, which is integral to inflammatory pain (67,68). Data suggests that psychedelics reduce inflammation (69)(70)(71) via the downstream effects of 5-HT2 A agonism such as TNF regulation (72), and may result in desensitized central pain responses (66). The acute effects of psychedelics may also contribute toward an analgesic response by reorienting attention away from unpleasant sensations toward altered perceptions, e.g., visual hallucinations (73). ...
Article
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Background: Chronic Pain is among the leading causes of disability worldwide with up to 60% of patients suffering from comorbid depression. Psychedelic-assisted therapy has recently been found effective in treating a host of mental health issues including depression and has historically been found to be useful in treating pain. Reports of self-medication for chronic pain using psychedelic drugs have been widely documented, with anecdotal evidence indicating widespread success in a range of pathologies. Aims: In preparation for an upcoming trial, to better understand how those with lived experience of chronic pain self-medicate with psychedelic drugs, and to establish, in detail, their therapeutic protocols and practices for success. Methods: As part of patient-involvement (PI) for an upcoming trial in this population, 11 individuals who reported self-medicating with psychedelic drugs took part in a 1-h semi-structured discussion, which was then transcribed and thematically analyzed. Results: Across a range of psychedelic substances and doses, reported pain scores improved substantially during and after psychedelic experiences. Two processes, Positive Reframing and Somatic Presence, were reliably identified as playing a role in improvements in mental wellbeing, relationship with pain, and physical (dis)comfort. Inclusion of other strategies such as mindfulness, breathwork, and movement were also widely reported. Due to the data's subjective nature, this paper is vulnerable to bias and makes no claims on causality or generalisability. Together, these results have been used to inform study design for a forthcoming trial. Conclusion: This pre-trial PI work gives us confidence to test psychedelic therapy for chronic pain in a forthcoming controlled trial. The results presented here will be instrumental in improving our ability to meet the needs of future study participants.
... In line with our observations suggesting non-neuronal populations' involvement, in particular of the immune system, psychedelics have been shown to exert anti-inflammatory effects, which led to their proposal as treatments for neurodegenerative diseases such as Alzheimer disease (Vann Jones and O'Kelly 2020;Family et al., 2020;Flanagan & Nichols, 2018). ...
Article
Full-text available
Psychedelic drugs are gaining attention from the scientific community as potential new compounds for the treatment of psychiatric diseases such as mood and substance use disorders. The 5‐HT2A receptor has been identified as the main molecular target, and early studies pointed to an effect on the expression of neuroplasticity genes. Analysing RNA‐seq data from the prefrontal cortex of rats chronically treated with lysergic acid diethylamide (LSD), we describe the psychedelic‐induced rewiring of gene co‐expression networks, which become less centralized but more complex, with an overall increase in signalling entropy typical of highly plastic systems. Intriguingly, signalling entropy mirrors, at the molecular level, the increased brain entropy reported through neuroimaging studies in human, suggesting the underlying mechanisms of higher‐order phenomena. Moreover, from the analysis of network topology we identify potential transcriptional regulators and propose the involvement different cell types in psychedelics’ activity.
... This ensures the reconnection of networks in a "healthy" manner (Kyzar et al., 2017). Other potential mechanisms include neuroendocrine (Schindler et al., 2018), anti-inflammatory (Flanagan & Nichols, 2018), and glutamatergic actions (Vollenweider & Kometer, 2010). Recently, it has been suggested that the mechanisms through which psychedelic drugs exert their therapeutic effects should be studied in light of the polypharmacology paradigm, since they display a complex, multi-target effect on several sites of the central nervous system . ...
Article
The Global Mental Health (GMH) movement aims to provide urgently needed treatment to those with mental illness, especially in low-and middle-income countries. Due to the complexity of providing mental health services to people from various cultures, there is much debate among GMH advocates regarding the best way to proceed. While biomedical interventions offer some degree of help, complementary approaches should focus on the social/community aspects. Many cultures conduct traditional rituals involving the communal use of psychoactive plants. We propose that these practices should be respected, protected, and promoted as valuable tools with regard to mental health care at the community level. The traditional use of psychoactive plants promotes community engagement and participation, and they are relatively affordable. Furthermore, the worldviews and meaning-making systems of local population are respected. The medical systems surrounding the use of psychoactive plants can be explained in biomedical terms, and many recently published clinical trials have demonstrated their therapeutic potential. Psychoactive plants and associated rituals offer potential benefits as complementary aspects of mental health services. They should be considered as such by international practitioners and advocates of the GMH movement.
... After more than 6 decades of research into and popular use of classic psychedelics (defined here as a class of drugs that produce a unique profile of subjective effects and have a principal site of action at the 5HT 2A receptor, such as LSD or psilocybin), recent promising trials investigating the effects of psilocybin therapy for the treatment of depression [1,2], anxiety and depression in cancer patients [3,4], tobacco smoking [5], and alcohol use disorder [6] have inspired additional medical, commercial, and public interest in using psychedelics as treatments for psychiatric disorders. Interest has also grown in understanding whether psilocybin therapy may be effective for a wider range of indications [7][8][9]. ...
Article
Introduction: Psychedelics show promise in treating unipolar depression, though patients with bipolar disorder have been excluded from recent psychedelic trials. There is limited information on the use of classic psychedelics (e. g., LSD or psilocybin) in individuals using mood stabilizers to treat bipolar disorder. This is important to know, as individuals with bipolar depression may attempt to treat themselves with psychedelics while on a mood stabilizer, particularly given enthusiastic media reports of the efficacy of psilocybin for depression. Methods: This study analyzed reports of classic psychedelics administered with mood stabilizers from 3 websites (Erowid.org, Shroomery.org, and Reddit.com). Results: Strikingly, 47% of 62 lithium plus psychedelic reports involved seizures, and an additional 18% resulted in bad trips while none of 34 lamotrigine reports did. Further, 39% of lithium reports involved medical attention. Most of the lamotrigine reports (65%) but few (8%) of the lithium reports were judged to not affect the psychedelic experience. Discussion: Although further research is needed, we provisionally conclude that psychedelic use may pose a significant seizure risk for patients on lithium.
... Flanagan et ai. notaram que os psicodélicos são anti-inflamatórios [20]. ...
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Portuguese translation of Turkia, Mika: Self-treatment of psychosis and complex post-traumatic stress disorder with LSD and DMT—A retrospective case study. Psychiatry Research Case Reports 2022;1(2):100029, https://doi.org/10.1016/j.psycr.2022.100029
... Vollenweider et al. ovat kuvanneet hoidon biokemiallisia mekanismeja, kokemusten laadun ennustamista, ja lyhyen ja pitkän aikavälin hoitotuloksia [19]. Flanagan et al. ovat todenneet, että psykedeelit ovat tulehdusta vähentäviä [20]. ...
Article
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Finnish translation of Turkia, Mika: Self-treatment of psychosis and complex post-traumatic stress disorder with LSD and DMT—A retrospective case study. Psychiatry Research Case Reports 2022;1(2):100029, https://doi.org/10.1016/j.psycr.2022.100029
... Second, classic psychedelics administered in a safe and supportive setting have been shown to improve mental health conditions associated with cardiometabolic diseases [12][13][14][15][16] . Third, classic psychedelics have anti-inflammatory and immunomodulatory properties of importance for both mental and cardiometabolic health [17][18][19][20] . Fourth, classic psychedelics have high affinity to serotonin receptor subtypes associated with cardiometabolic diseases (e.g., serotonin 2A and 2C receptors) 17,21 . ...
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The objective of the current study was to investigate the associations between lifetime classic psychedelic use and cardiometabolic diseases. Using data from the National Survey on Drug Use and Health (2005–2014), the present study examined the associations between lifetime classic psychedelic use and two types of cardiometabolic disease: heart disease and diabetes. Respondents who reported having tried a classic psychedelic at least once in their lifetime had lower odds of heart disease in the past year (adjusted odds ratio (aOR) = 0.77 (0.65–0.92), p = .006) and lower odds of diabetes in the past year (adjusted odds ratio (aOR) = 0.88 (0.78–0.99), p = .036). Classic psychedelic use might be beneficial for cardiometabolic health, but more research is needed to investigate potential causal pathways of classic psychedelics on cardiometabolic diseases.
... Interestingly, both mesenchyme-and immune-related modules display similar topological restructuring. In line with our observations suggesting non-neuronal populations' involvement, in particular of the immune system, psychedelics have been shown to exert anti-inflammatory effects, which led to their proposal as treatments for neurodegenerative diseases such as Alzheimer disease (Family et al., 2020;Flanagan & Nichols, 2018;Vann Jones & O'Kelly, 2020). . CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. ...
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Psychedelic drugs are gaining attention from the scientific community as potential new compounds for the treatment of psychiatric diseases such as mood and substance use disorders. The 5-HT2A receptor has been identified as the main molecular target, and early studies pointed to an effect on the expression of neuroplasticity genes. Analysing RNA-seq data from the prefrontal cortex of rats chronically treated with lysergic acid diethylamide (LSD), we describe the psychedelic-induced rewiring of gene co-expression networks, which become less centralized but more complex, with an overall increase in signalling entropy, typical of highly plastic systems. Intriguingly, signalling entropy mirrors, at the molecular level, the increased brain entropy reported through neuroimaging studies in human, suggesting the underlying mechanisms of higher-order phenomena. Moreover, from the analysis of network topology we identify potential transcriptional regulators and imply different cell types in psychedelics' activity.
... Por otra parte, el mecanismo de acción responsable de la eficacia de las sustancias mencionadas no está claro. En cuanto a las indolaminas consideradas (psilocibina y LSD), se ha planteado que su acción agonista a los receptores 5-HT 2A podría estar mediando los efectos clínicos sobre la migraña (Sewell, 2020), en consonancia con los resultados obtenidos en estudios con modelos animales, donde se ha constatado que la activación de dichos receptores provoca efectos antiinflamatorios (Flanagan & Nichols, 2018). Las alteraciones en el sueño se encuentran bajo investigación, pero puede formar parte de la fisiopatología de las cefaleas, donde los receptores 5-HT 2A también muestran su implicación, por lo que podría estar relacionado con el potencial terapéutico de estas sustancias (Schindler et al., 2018). ...
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Los alucinógenos incluyen a un grupo heterogéneo de sustancias que provocan cambios en la percepción sensorial, el pensamiento y la consciencia. El potencial terapéutico de diversas drogas alucinógenas está recibiendo un interés creciente en los últimos años. En este trabajo presentamos una revisión bibliográfica centrada en el posible uso de los alucinógenos (LSD, psilocibina y ketamina) en el tratamiento y prevención de las cefaleas. Para ello, se ha realizado unabúsqueda (sin límite temporal) en las bases de datos de Web of Sciences, Scopus y Pubmed, además de una búsqueda manual en las referencias de los artículos. Los resultados constatan la eficacia del LSD, especialmente a nivel profiláctico, mientras que la ketamina podría ser de utilidad para abortar los ataques agudos y la psilocibina ha demostrado ser efectiva en ambos aspectos. Los estudios existentes se han llevado a cabo principalmente en pacientes con migraña y con cefalea en racimos, entre otros tipos de cefaleas. Asimismo, se señalan diversas limitaciones metodológicas que pueden dificultar la generalización de los resultados, y se sugiere la necesidad de realizar futuras investigaciones en este campo emergente.
... [1] reducing ROS production, [2] reducing inflammation, [3] modulating growth factors and neurotransmitter signaling, and subsequently [4] modulating neuroplasticity. Each of these effects could be driven by 5-HT2AR agonism, [80][81][82][83] but each could also be enhanced by concurrent sigma-1 receptor agonism (Sup. Fig. 20). ...
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Post-traumatic stress disorder (PTSD) is associated with cognitive deficits, oxidative stress and inflammation. N,N-dimethyltryptamine (DMT) is a known neuroprotective, antioxidant, anti-inflammatory, and psychoplastogen with antidepressant effects. Therefore, we tested the capacity of DMT, the monoamine oxidase inhibitor (MAOI) harmaline, and “pharmahuasca” (DMT + harmaline) to reduce reactive oxygen species (ROS) production and inflammatory gene expression and modulate neuroplasticity-related gene expression in a predator exposure and psychosocial stress rat model of PTSD. We administered DMT (2 mg/kg IP), harmaline (1.5 mg/kg IP), or pharmahuasca every other day for 5 days. We measured ROS production in the prefrontal cortex (PFC) and hippocampus (HC) by electron paramagnetic resonance spectroscopy (EPR) and extracted total RNA from the PFC for sequencing. We also performed in vitro assays to measure the affinity and efficacy of DMT and harmaline at the 5HT2AR. DMT and pharmahuasca reduced ROS production in the PFC and HC, while harmaline had mixed effects. RNA sequencing implicated genes related to ROS production, inflammation, neurotransmission, and neuroplasticity. DMT, but not harmaline exhibits both affinity and efficacy at the human 5HT2AR. DMT and pharmahuasca exhibit broad effects that may facilitate the treatment of PTSD by reducing ROS production and inflammatory gene expression, and inducing neuroplasticity.
... In contrast to ketamine, SHs as a class exhibit potent anti-inflammatory effects across a myriad of disease models and cell lines [191][192][193][194]. The most studied SH with regards to inflammation, 2,5-dimethoxy-4-iodoamphetamine (DOI), has been shown to profoundly suppresses TNF-α mediated inflammation in rodent tissues at picomolar concentrations-equating to a dose in humans at least two orders of magnitude below what is necessary to produce hallucinogenic effects [185,193,194]. ...
Article
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Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with a high individual and societal burden. While not all patients display overt markers of elevated inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease, and likely explains the elevated rates of comorbid inflammatory illnesses seen in this population. While individual systems have been intensely studied and targeted, a relative paucity of attention has been given to the interconnecting role of inflammatory signals therein. This review presents an updated overview of some of the most prominent pathophysiologic mechanisms in bipolar disorder, from mitochondrial, endoplasmic reticular, and calcium homeostasis, to purinergic, kynurenic, and hormonal/neurotransmitter signaling, showing inflammation to act as a powerful nexus between these systems. Several areas with a high degree of mechanistic convergence within this paradigm are highlighted to present promising future targets for therapeutic development and screening.
... We also acknowledge there are many alternative models accounting for the efficacy of PAP (e.g. Flanagan & Nichols, 2018;Hartogsohn, 2016;Olson, 2018;Vollenweider & Preller, 2020). However, a full review of these would be beyond the scope of the paper. ...
Preprint
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Recent clinical trials have demonstrated that psilocybin may have strong antidepressant effects, and may be effective in the treatment of depressive disorders when embedded in a psychotherapeutic protocol (psychedelic-assisted psychotherapy; PAP). There are now dozens of registered and ongoing clinical trials that intend to test for the efficacy of psilocybin within a psychotherapeutic protocol. Despite promising results, the mechanism(s) that may be responsible for the antidepressant effects of PAP are still hotly contested. In this paper, we provide a broad overview of the recent clinical work conducted with psychedelics on depressive disorders, and summarise several theories of action of PAP. Extending on the state of the field, we argue that the ‘Network Theory of Mental Disorders’ is a useful tool for clinical research with psychedelics. We hypothesise that, if PAP is successful, the connections between symptoms in a network will weaken, thereby rendering the patient less vulnerable to developing or relapsing into depression. We argue that application of the Network Theory may (a) provide deeper insights into the effects of PAP on specific symptom interactions, both on an interindividual and intraindividual basis, (b) generate fruitful hypotheses for the clinical action of PAP, and (c) provide a pre-emptive tool for making the most of ‘intentions’ preceding and during psychedelic experiences. These findings we hope will ultimately improve responsiveness and reduce relapse in response to this promising therapy.
... The etiology of OCD is still unclear, yet it is proposed to be a complicated process, which involves an interaction between multiple factors. These include genetic, inflammatory, and environmental facets [4]. Some studies have recently speculated that the pathogenesis of OCD could be linked to autoimmune and rheumatological disruptions [5]. ...
Article
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Obsessive-compulsive disorder (OCD) is a common mental illness that can significantly impair the patients' quality of life. Recent studies have shown that patients with this condition usually suffer from inflammatory or rheumatological comorbidities. However, the association between OCD's etiology and inflammation is still controversial. This review aims to explore the correlation between OCD and rheumatological as well as inflammatory disorders based on studies conducted in the last decade. A total of eight articles that were deemed eligible were included in the final assessment, involving 31,204 OCD patients from various countries. The most significant inflammatory biomarkers examined were tumor necrosis factor-alpha (TNF-α), interleukins, neutrophil-to-lymphocyte ratio (NLR), and cytokines. We concluded that the pathophysiology and etiology of OCD are strongly correlated with inflammatory biomarkers. This finding warrants future studies on the efficacy of anti-inflammatory agents to treat OCD, particularly in the early stages of the disease.
... Some research has shown psychedelics capable of improving brain-derived neurotrophic factor (BDNF) with resultant positive effects on synaptic plasticity. Psilocybin promotes network disintegration and anti-inflammatory action involving transient bottom-up processes [1,47]. It also has a neuro-modulatory effect that enhances cognitive reasoning and may contribute to personal intuitions reducing negative thoughts [43,48]. ...
Article
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Introduction: Psilocybin mushroom use is well documented in spiritual and religious ceremonies globally. This drug is now the most popular in Europe and the USA. Objective: The objective of this study is to explore the experiences and effects of psilocybin on patients with depression and anxiety. Method: A qualitative study was conducted interviewing ten participants currently taking psilocybin while experiencing depression and/or anxiety. Ethical approval was obtained from the University ethics committee. Participants were recruited via social media and groups are known to have used psilocybin for the treatment of anxiety and/or depression. Participants were informed of study aims and consent was obtained before interviews commenced. Confidentiality was maintained throughout this study. Interviews began with informing participants that psilocybin may be effective in the management of depression. Initially, information around the way treatment with psilocybin was obtained was sought. This was followed by queries around the effects of the drug in terms of experiences both during and after treatment. Finally, participants were asked to outline the positive effects of psilocybin on their lives. Results: The data were thematically coded using Grounded Theory as an underpinning philosophical paradigm. Emerging themes included enhancement of smell, vision, hearing, and taste sensations. Another theme emerging was the experience of being ‘connected with the universe’ while on the drug. Additionally, participants reported a stabilization of mood, an increase in optimism and emotional control, and a healthier emotional connection with others. Most also felt an increase in comfort, peace and calmness. Another theme that emerged centered on the mechanism of action of psilocybin. Participants stated that this substance seemed to ‘make new connections in their brain,’ resulting in new perspectives. Some participants felt this resulted in a calming influence on the mind and body. This aligns with research showing that psilocybin works by changing the thinking and improving information processing. Conclusion: Psilocybin has promising effects on the patients with depression/anxiety even after a single dose. Psilocybin is safe but the administration should be guided by a health professional to yield safe and positive outcomes.
... These include the potential to promote neural plasticity 9 (i.e., psychoplastogenic effects) and the ability to dampen immune responses. 10 The first SAR study aiming to characterize the psychoplastogenic pharmacophore of psychedelics was published last year, 11 and here, Nichols and coworkers used a rodent model of allergic asthma to better define the anti-inflammatory pharmacophore. 12 Excitingly, they found that there is no correlation between anti-inflammatory and hallucinogenic effects, suggesting that psychedelics might be used as lead structures to identify nonhallucinogenic compounds capable of reducing inflammation. ...
... These findings are especially remarkable regarding the treatment of depression, given the increased expression of pro-inflammatory cytokines found in patients diagnosed with major depressive disorder [157], as well as evidence that the administration of IFNα and other inflammatory cytokines to healthy individuals induces symptoms of depression [158,159]. However, the anti-inflammatory effects of PE are also relevant for the treatment of other pathologies involving inflammatory processes, such as asthma [152] and neurodegenerative diseases [160], among others. ...
Chapter
Interest in psychoactive ethnobotanicals such as ayahuasca or Psilocybe mushrooms for clinical uses has increased over the last two decades. While clinical and experimental approaches have focused on using isolated compounds of interest (such as psilocybin), an emerging trend in drug discovery involves a more comprehensive approach. The polypharmacology paradigm, as it has been named, suggests that promiscuous drugs could be safer and more effective than highly selective ones. This is especially relevant with regards to complex diseases, like most mental health problems and neurodegenerative diseases, and for natural products, including psychoactive ethnobotanicals. Natural products not only show a multi-target profile, but they also contain several compounds capable of interacting with one another and producing synergistic effects. In this chapter, the use of whole natural products instead of isolated compounds is suggested in support of combining two recent paradigms: psychedelic-assisted therapy on the one side and polypharmacology on the other.
... Recent studies in animal models suggest that psychedelics may also display a broader spectrum of applications in neuronal damage and neuropsychiatric conditions such as Traumatic Brain Injury (TBI), Alzheimer's Disease (AD), and others (Scott and Carhart-Harris, 2019;Vann Jones and O'Kelly, 2020). Their therapeutic effects are related to immunomodulatory potential, ability to induce neurogenesis, and neural plasticity; however exact mechanisms are yet to be identified (Flanagan and Nichols, 2018;Ly et al., 2018). ...
Preprint
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Psychedelics are new, promising candidate molecules for clinical use in psychiatric disorders such as Treatment-Resistant Depression (TRD) and Post Traumatic Stress Disorder (PTSD). They were recently also proposed as molecules supporting neural tissue repair by anti-inflammatory properties. Here we reported that two classic psychedelics, DMT and psilocin, can influence microglial functions by reducing the level of TLR4, p65, CD80 proteins, which are markers of the immune response, and upregulat TREM2 neuroprotective receptor. Psilocin also secured neuronal survival in the neuron-microglia co-culture model by attenuating the phagocytic function of microglia. We conclude that DMT and psilocin regulate the immunomodulatory potential of microglia. Of note, psychedelics were previously reported as a relatively safe treatment approach. The demonstrated regulation of inflammatory molecules and microglia phagocytosis suggests that psychedelics or their analogs are candidates in the therapy of neurological disorders where microglia and inflammation significantly contribute to pathogenic disease mechanisms.
... Although serotonin is known to have pro-inflammatory effects throughout the body, 5-HT 2A agonism by classic psychedelics such as LSD and (R)-2,5dimethoxy-4-iodoamphetamine (DOI) has been shown to suppress TNFα expression and nuclear translocation of NF-κB in vitro, with similar findings in vivo (Nau Jr et al., 2013;Yu et al., 2008). Flanagan and Nichols (2018) hypothesize that these effects can be explained by functional selectivity, meaning that different agonists at the same receptor can produce different downstream effects. In the case of psychedelics, binding at 5-HT 2A may result in recruiting antiinflammatory pathways rather than pro-inflammatory pathways typically activated by serotonin. ...
... Psychedelics modulate the immune system via 5-HT1, 5-HT2, and sigma-1 receptor activity (18,233,(241)(242)(243)(244)(245)(246)(247)(248). Altered immune system function, mainly characterized by chronic lowgrade inflammation is associated with a range of psychiatric disorders (57,(249)(250)(251) and it remains an open question whether the potential anti-inflammatory activity of psychedelics will play a role in autoimmune disorders (252) or chronic pain (253,254). ...
Article
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Accumulating clinical evidence shows that psychedelic therapy, by synergistically combining psychopharmacology and psychological support, offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and/or maladaptive habitual patterns of emotion, cognition and behavior, notably, depression (MDD), treatment resistant depression (TRD) and addiction disorders, but perhaps also anxiety disorders, obsessive-compulsive disorder (OCD), Post-Traumatic Stress Disorder (PTSD) and eating disorders. Despite the emergent transdiagnostic evidence, the specific clinical dimensions that psychedelics are efficacious for, and associated underlying neurobiological pathways, remain to be well-characterized. To this end, this review focuses on pre-clinical and clinical evidence of the acute and sustained therapeutic potential of psychedelic therapy in the context of a transdiagnostic dimensional systems framework. Focusing on the Research Domain Criteria (RDoC) as a template, we will describe the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, traversing molecular, cellular and network levels. These levels will be mapped to the RDoC constructs of negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems. In summarizing this literature and framing it transdiagnostically, we hope we can assist the field in moving toward a mechanistic understanding of how psychedelics work for patients and eventually toward a precise-personalized psychedelic therapy paradigm.
... Instead, they possess powerful anti-inflammatory and neuroprotective effects (Tang & Tang, 2019). Given the established relationship between inflammation and depression (Miller, Maletic, & Raison, 2009), together with the well-known and powerful anti-inflammatory effect of serotonergic psychedelics (Flanagan & Nichols, 2018;Yu et al., 2008), these findings could be relevant in the case of psilocybin and lead to the consideration of other targets in addition to those associated with its psychoactive effects when describing its mechanisms of action. ...
Article
While the field of psychedelic research is continuously expanding and offers new hope for achieving successful treatments for physical and mental disorders, certain methodological aspects require improvement. Some of the flaws are shared with clinical trials for other kinds of drugs and others are specific to the field. Given that psychedelic research is an emerging field, it is important to address these problems in a timely manner. In this manuscript, we present the main methodological issues in psychedelic research, ranging from the most manageable (e.g., non-representative samples) to the most complex (e.g., limitations of the biomedical model). In addition, given its relevance, we dedicate a section of the manuscript to a discussion of ethical concerns around psychedelic research.
... Vollenweider et al. have provided an overview of biological mechanisms, predictors of psychedelic experience, as well as acute and long-term outcomes ( Vollenweider and Smallridge, 2022 ). Flanagan et al. have noted that psychedelics are antiinflammatory ( Flanagan and Nichols, 2018 ). ...
Article
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Please note: compared to the preprint, this article has been significantly updated and extended. It now includes discussions about the role of self-treatment, harm reduction approach, alternative models of psychedelic therapy, and the role of case studies.
... Regarding pro-inflammatory cytokines, ayahuasca significantly decreased CRP levels 2 days after treatment in both healthy volunteers and depressed patients but did not change IL-6 levels in any sample [40]. Although preclinical studies demonstrate that 5HT 2A receptor agonists have prominent anti-inflammatory properties [76,77], studies in humans quantifying inflammatory biomarkers are still scarce. A previous meta-analysis found that only 58% of depressed patients showed mildly elevated CRP levels [78]. ...
Article
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Although results are still preliminary, ketamine and classical hallucinogens have shown promise in recent years as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression (TRD). Depression also seems to be related to abnormal levels of peripheral inflammatory and neurotrophic biomarkers, which may one day help to diagnose of this disorder. In this context, this systematic review of clinical trials evaluated the current evidence that relates the antidepressant effects of ketamine and classical hallucinogens on TRD with changes in inflammatory and neurotrophic biomarkers. Twelve studies were found (n=587), 2 with oral ayahuasca (1 mL/kg) and 10 with ketamine (mostly intravenous 0.5 mg/kg) administration. Results for all biomarkers assessed were contradictory and thus inconclusive. Randomized controlled trials with bigger samples and higher statistical power are warranted to clarify if peripheral biomarkers can confidently be used to indicate and measure ketamine’s and classical hallucinogens’ antidepressant effect. The PROSPERO ID for this study is CRD42021249089.
... The available literature on the immunomodulatory properties of psychedelic tryptamines is scarce and mostly confined to preclinical studies(Flanagan & Nichols, 2018;Kyzar et al., 2017). A small number of existing studies, by combining in vitro assays and in silico analyses, have demonstrated the anti-inflammatory properties of DMT and 5-MeO-DMT(Tourino et al., 2013;Szabo et al., 2014;Dakic et al., 2017). ...
Article
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5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT) is a naturally occurring tryptamine that primarily acts as an agonist at the 5‐HT1A and 5‐HT2A receptors, whereby affinity for the 5‐HT1A subtype is highest. Subjective effects following 5‐MeO‐DMT administration include distortions in auditory and time perception, amplification of emotional states and feelings of ego dissolution that usually are short lasting, depending on the route of administration. Individual dose escalation of 5‐MeO‐DMT reliably induces a “peak” experience, a state thought to be a core predictor of the therapeutic efficacy of psychedelics. Observational studies and surveys have suggested that single exposure to 5‐MeO‐DMT can cause rapid and sustained reductions in symptoms of depression, anxiety and stress. 5‐MeO‐DMT also stimulates neuroendocrine function, immunoregulation and anti‐inflammatory processes, which may contribute to changes in mental health outcomes. To date, only one clinical trial has been published on 5‐MeO‐DMT, demonstrating safety of vaporised dosing up to 18mg. Importantly, the rapid onset and short duration of the 5‐MeO‐DMT experience may render it more suitable for individual dose finding strategies as compared to longer acting psychedelics. A range of biotech companies have shown an interest in the development of 5‐MeO‐DMT formulations for a range of medical indications, most notably depression. Commercial development will therefore be the most important resource for bringing 5‐MeO‐DMT to the clinic. However fundamental research will also be needed to increase understanding of the neurophysical and neural mechanisms that contribute to the potential clinical effects of 5‐MeO‐DMT and its sustainability and dissemination over time. Such studies are less likely to be conducted as part of drug development programs and are more likely to rely on independent, academic initiatives.
... 68 The precise mechanism of this role is not known but some researchers have proposed a mechanism of functional selectivity to recruit unique effector pathways, perhaps serotonin activation turn on inflammatory response in 5-HT receptors but certain phsychedelics mediated stimulation of 5 -HT receptor causes opposite response. [69][70] 4.2 Sigma 1 receptor : ...
Preprint
In search of cure for neurological disorders a previously abandoned class of medications called Psychedelic and their active derivatives particularly Psilocybin, a tryptamine like compound has regained the research interest. Emerging scientific evidence support the psychedelic therapeutic benefits beyond Major depressive disorder (MDD) and substance use disorder (SUD). Recently collected encouraging results have already led to bestow these agents with a "Breakthrough Therapy" status by FDA for long term treatment of major psychiatric illness particularly MDD. Additionally, in vivo and in vitro research findings points towards psychedelic therapeutic potential for treatment and prevention of close brain injury and neurodegenerative disorders such as Alzheimer disease. Although psychedelic's complete molecular mechanism imparting there therapeutic effect is yet to be determined but preclinical work has uncovered the psychedelic ability to induce neural progenitor cell proliferation, spinogenesis, synaptic rebirth and increase in neuroplasticity via various complex biochemical mechanisms. These agents have also demonstrated significant immunomodulator potential by reducing pro inflammatory agents such as tumor necrosis factor alpha (TNF-α), Interleukin1-Beta (IL-β) and Interlukin-6 (IL-6) contributing to their healing power. Although the definite role of psychedelic benefits beyond MDD and SUD yet to be determine, but if scientific data is successfully replicated in clinical trials psychedelics can develop into revolutionary treatment modality for multiple neuropsychiatric conditions along with previously approved treatment of psychiatric disorder. In this review author discuss recent scientific research and study results pertaining to psychedelics therapeutic effects at cellular level in central nervous system with emphasis on neurodegeneration. Abbreviations/ Keywords: BDNF; Brain-derived neurotrophic factor, BBB; Blood-brain barrier, CNS; Central nervous system, DMT; N,N dimethyl tryptamine, ERS; Endoplasmic reticulum stress, FDA; food and drugs administration, fMRI; Functional magnetic resonance imaging, IL; interleukin, LSD; Lysergic acid diethyl amide, MMD; Major depressive disorder, Nrf2; Nuclear factor erythroid2-related factor 2, Rac 1; Rat-related C3 botulinum toxin substrate 1, RhoA; Ras homolog family member A, TAAR; Trace amine-associated receptor, Tj; Tight junction, Tumor necrosis factor alpha (TNF-α), Tropomyosin receptor kinase B; (TrkB). SUD; Substance use disorder. Method: To investigate the role of Psychedelic in neurodegeneration the PubMed and Google scholar databases were searched for terms like psychedelic, 5-HT receptor serotonin, neuropsychiatric role of psychedelics, recent clinical trial and psychedelic, neuroprotection, immunomodulation, neurodegenerative mechanisms , psychedelic and recent break through studies and treatments. Additional search of reference articles was carried out and related articles were chosen for review Pertinent articles describing the historical preview, biochemical properties, mechanism of action of Psychedelic in neuro psychiatric conditions and their effect on related symptoms in different settings, both in vivo and in vitro models were selected. Only reviews, analyses, meta-analyses, and randomized control-based studies were included in the search criteria. The focus of the search was on adults, regardless of specific age, race, or gender. Only articles written in English, published within last ten years and with free access were included.
... Conversely, SHs consistently appear to exert potent anti-inflammatory effects across many different disease models and cell lines [52][53][54][55] . 2,5-dimethoxy-4-iodoamphetamine (DOI), a synthetic derivative of mescaline, is perhaps the most-studied SH with regards to inflammation. ...
Article
While psychedelic-assisted therapies are currently being studied for several indications in clinical trials, there is legal and ethical ambiguity for mental health professionals concerning these compounds. Seventy-six mental health professionals completed an online survey asking them to rank their interest in topics related to psychedelic therapy, research, legal obstacles, barriers to incorporating psychedelics in practice, and terminology related to the field. Results showed that providers want more clearly defined terminology and operating procedures concerning business matters such as malpractice and clinic guidelines, legal and ethical clarity on administering psychedelics in private practice and integration work, and further opportunities for psychedelic therapy training. The survey responses were reflected upon through the legal and ethical lens of the current psychedelic landscape.
... Psychedelic drugs are making a strong come-back in the research, clinical, and public spheres. Studies carried out in the past two decades suggest psychedelic drugs as potential therapeutics for depression (Carhart-Harris et al., 2016a), anxiety (Gasser et al., 2014), substance use disorders (de Veen et al., 2017) such as tobacco addiction (Johnson et al., 2017) or alcoholism (Bogenschutz et al., 2015), post-traumatic stress disorder , obsessive-compulsive disorder (Moreno et al., 2006), anorexia (Foldi et al., 2020), and inflammatory syndromes (Flanagan and Nichols, 2018). Promising results are giving patients hope of relieving the burden inflicted by their conditions. ...
Article
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Psychedelic compounds hold the promise of changing the face of neuroscience and psychiatry as we know it. There have been numerous proposals to use them to treat a range of neuropsychiatric conditions such as depression, anxiety, addiction and PTSD; and trials to date have delivered positive results in favor of the novel therapeutics. Further to the medical use, the wider healthy population is gaining interest in these compounds. We see a surge in personal use of psychedelic drugs for reasons not limited to spiritual enhancement, improved productivity, aiding the management of non-pathological anxiety and depression, and recreational interests. Notably, microdosing—the practice of taking subacute doses of psychedelic compounds—is on the rise. Our knowledge about the effects of psychedelic compounds, however, especially in naturalistic settings, is still fairly limited. In particular, one of the largest gaps concerns the acute effects on cognition caused by psychedelics. Studies carried out to date are riddled with limitations such as having disparate paradigms, small sample sizes, and insufficient breadth of testing on both unhealthy and healthy volunteers. Moreover, the studies are majoritarily limited to laboratory settings and do not assess the effects at multiple dosages within the same paradigm nor at various points throughout the psychedelic experience. This review aims to summarize the studies to date in relation to how psychedelics acutely affect different domains of cognition. In the pursuit of illuminating the current limitations and offering long-term, forward-thinking solutions, this review compares and contrasts findings related to how psychedelics impact memory, attention, reasoning, social cognition, and creativity.
... From these and other studies, it can be speculated that modulation of 5-HT associated pathways either via these identified targets or through 5-HT receptor agonism/antagonism may be exploited therapeutically to ameliorate viral-and immune-mediated ocular diseases. Indeed, several 5-HT receptor agonists and antagonists have been shown to have anti-inflammatory activity (Tullis et al., 2015;Flanagan and Nichols, 2018;Flanagan et al., 2019a,b;Yu et al., 2021). Given the current pandemic, it is notable that severe COVID-19 patients, who also can present with ocular manifestations, exhibit elevated peripheral serotonin levels. ...
Article
Full-text available
Herpes simplex virus-associated diseases are a complex interaction between cytolytic viral replication and inflammation. Within the normally avascular and immunoprivileged cornea, HSV ocular infection can result in vision-threatening immune-mediated herpetic keratitis, the leading infectious cause of corneal blindness in the industrialized world. Viral replicative processes are entirely dependent upon numerous cellular biosynthetic and metabolic pathways. Consistent with this premise, HSV infection was shown to profoundly alter gene expression associated with cellular amino acid biosynthetic pathways, including key tryptophan metabolism genes. The essential amino acid tryptophan is crucial for pathogen replication, the generation of host immune responses, and the synthesis of neurotransmitters, such as serotonin. Intriguingly, Tryptophan hydroxylase 2 (TPH2), the neuronal specific rate-limiting enzyme for serotonin synthesis, was the most significantly upregulated gene by HSV in an amino acid metabolism PCR array. Despite the well-defined effects of serotonin in the nervous system, the association of peripheral serotonin in disease-promoting inflammation has only recently begun to be elucidated. Likewise, the impact of serotonin on viral replication and ocular disease is also largely unknown. We therefore examined the effect of HSV-induced serotonin-associated synthesis and transport pathways on HSV-1 replication, as well as the correlation between HSV-induced ocular serotonin levels and disease severity. HSV infection induced expression of the critical serotonin synthesis enzymes TPH-1, TPH-2, and DOPA decarboxylase (DDC), as well as the serotonin transporter, SERT. Concordantly, HSV-infected cells upregulated serotonin synthesis and its intracellular uptake. Increased serotonin synthesis and uptake was shown to influence HSV replication. Exogenous addition of serotonin increased HSV-1 yield, while both TPH-1/2 and SERT pharmacological inhibition reduced viral yield. Congruent with these in vitro findings, rabbits intraocularly infected with HSV-1 exhibited significantly higher aqueous humor serotonin concentrations that positively and strongly correlated with viral load and ocular disease severity. Collectively, our findings indicate that HSV-1 promotes serotonin synthesis and cellular uptake to facilitate viral replication and consequently, serotonin’s proinflammatory effects may enhance the development of ocular disease.
... A recent study has shown that these psychedelics do cause robust increase in the dendrites and spines of cortical neurons (Ly et al., 2018), which may explain why resurgent clinical work with this class of compounds shows excellent outcomes in treating depression and anxiety (Osório Fde et al., 2015;Carhart-Harris et al., 2016;Griffiths et al., 2016). Moreover, psychedelics possess potent anti-inflammatory properties (Flanagan and Nichols, 2018). It is tempting to speculate that this class of drug may improve the outcome of GIDD, particularly in individuals in which ACC hyperactivity is contributing top-down exacerbation of gut dysfunction. ...
Article
Most gastrointestinal diseases and disorders (GIDD) are associated with depression, anxiety, and cognitive dysfunction. This suggests that shared features of GIDD, particularly chronic pain and inflammation, affect specific neural targets. The critical review of clinical and animal research presented here reveals that anterior cingulate cortex (ACC) is a primary target. It is particularly sensitive to neuroinflammation, and its function accounts for altered mental function emergent in GIDD. We propose that peripherally-triggered neuroinflammation normally signals injury/illness to ACC, which increases threat assessment and pain sensitivity to cope with increased vulnerability. Chronic peripheral inflammation over-drives this process, leading to long-term ACC structural remodeling, and excessive threat signaling. This evokes anxiodepressive phenotypes even without direct evidence of threats because ACC utilizes schemas to infer affective outcomes (e.g. pain) based on complex contextual information. This activates the autonomic nervous system, exacerbates immune dysfunction, and promotes further gut pathology. This theory provides a mechanistic account of bidirectional interactions among gastrointestinal, immunological, and neural systems in GIDD, and is likely applicable to other chronic inflammatory conditions.
... Depression has been associated with low-grade inflammation; correspondingly, psychedelics, i.e. 5-HT 2A receptor agonists, have been found to be powerful anti-inflammatory agents. Flanagan and Nichols have hypothesized that psychedelics acutely reset resting state functional connectivity (rsFC) to healthy networks to rapidly alleviate depression, then produce long-lasting effects by reducing neuroinflammation and preventing the brain from returning to a persistent inflamed pathological state and the accompanying depression [29]. ...
Preprint
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This article presents a case of a woman in her early forties with early complex trauma due to domestic violence, sexual abuse and poverty in her childhood, resulting in approximately three decades of treatment resistant depression. Antidepressive medications did not alleviate her depression but resulted in adverse effects and an eventual discontinuation of the medications. Eventually the woman resorted to 'mixed-method' underground small-group sessions that utilized breathing exercises, cold exposure, physical exercises, music, and psilocybin mushrooms. Psilocybin appeared to interrupt trauma-related dissociation, producing an 'anti-dissociative' effect, allowing the woman to re-experience, in a controlled setting, dissociated physical sensations produced by earlier overwhelming events. After a period of approximately 1.5 years, during which time she had six psilocybin sessions, either individually, in the small group, or with friends, she achieved a remission of her depression. A follow-up interview 2.5 years later indicated permanence of the result. Information was acquired from semi-structured retrospective interviews with a total duration of approximately eight hours. This case study may facilitate an improved understanding of the requirements for and the process of alleviating or resolving treatment-resistant depression with psychedelics. Recent clinical trials have utilized one or two doses of psilocybin. This case illustrates the need for adopting a multi-dose strategy over an extended period of time in order to achieve remission.
... Animal studies have suggested that psychedelics increase neuroplasticity, possibly through increased cortical glutamate, brain-derived neurotrophic factor, and activation of the tropomyosin receptor kinase B [34,38,39]. Other animal studies have proposed that psychedelics may elicit their antidepressant effect through antiinflammatory processes, by inhibiting proinflammatory cytokines TNF-α and IL-6, which have been found to be associated with depression [40]. However, more research is required to comprehensively understand how psychedelics may be acting on the brain to alleviate depressive symptoms. ...
Article
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Background There is currently renewed interest in the use of psychedelic therapy in the treatment of psychiatric disorders, including depression. The proposed systematic review will aim to identify, evaluate and summarise the psychological processes of change underlying psychedelic therapy for depression in the current literature and consider the implications these processes may have on the psychotherapy component of treatment. Methods Scopus, PsycINFO, PubMed and Web of Science databases will be searched using relevant terms. Studies will be included if they discuss the use of a classic psychedelic to treat depression symptomology in an adult population and report or propose psychological processes responsible for depression symptom change. Two authors will independently screen articles, complete quality assessment tools and conduct data extraction. Empirical and non-empirical research will be extracted and synthesised separately. A narrative synthesis approach will be used to report psychological processes identified in the literature. Discussion This systematic review will be the first to collate available evidence on the psychological processes associated with psychedelic therapy for depression. The preliminary nature of this research field is expected to result in the review having several limitations, namely heterogeneity between studies and the inclusion of limited empirical research. We intend for this review to present the current state of the literature, identify gaps and generate candidate variables that warrant further investigation. Systematic review PROSPERO CRD42020197202
... However, lisuride, a drug with a high affinity for 5-HT2AR and 5-HT2CR, produces no psychedelic effects (Pieri et al., 1978). This suggests that the functionally selective effects of serotonergic psychedelics on the 5-HT2AR differentially activate downstream second messenger signalling pathways to mediate subjective effects (Flanagan and Nichols, 2018). ...
Article
Full-text available
Background Postpartum depression (PPD) is a major public health concern and has, at its core, a sense of maternal ‘disconnection’ – from the self, the infant, and the support system. While PPD bears similarities with MDD, there is increasing evidence for its distinct nature, especially with the unique aspect of the mother-infant relationship. Current treatment modalities for PPD, largely based on those used in major depressive disorder (MDD), have low remission rates with emerging evidence for treatment resistance. It is, therefore, necessary to explore alternative avenues of treatment for PPD. Objective In this narrative review, we outline the potential therapeutic rationale for serotonergic psychedelics in the treatment of PPD, and highlight safety and pragmatic considerations for the use of psychedelics in the postpartum period. Methods We examined the available evidence for the treatment of PPD and the evidence for psychedelics in the treatment of MDD. We explored safety considerations in the use of psychedelics in the postpartum period. Results There is increasing evidence for safety, and encouraging signals for efficacy, of psilocybin in the treatment of MDD. Psilocybin has been shown to catalyse a sense of ‘reconnection’ in participants with MDD. This effect in PPD, by fostering a sense of ‘reconnection’ for the mother, may allow for improved mood and maternal sensitivity towards the infant, which can positively impact maternal role gratification and the mother-infant relationship. Conclusion Psychedelic assisted therapy in PPD may have a positive effect on the mother-infant dyad and warrants further examination.
Article
Psychedelic substances have played important roles in diverse cultures, and ingesting various plant preparations to evoke altered states of consciousness has been described throughout recorded history. Accounts of the subjective effects of psychedelics typically focus on spiritual and mystical-type experiences, including feelings of unity, sacredness, and transcendence. Over the past two decades, there has been increasing interest in psychedelics as treatments for various medical disorders, including chronic pain. Although concerns about adverse medical and psychological effects contributed to their controlled status, contemporary knowledge of psychedelics suggests that risks are relatively rare when patients are carefully screened, prepared, and supervised. Clinical trial results have provided support for the effectiveness of psychedelics in different psychiatric conditions. However, there are only a small number of generally uncontrolled studies of psychedelics in patients with chronic pain (e.g., cancer pain, phantom limb pain, migraine, and cluster headache). Challenges in evaluating psychedelics as treatments for chronic pain include identifying neurobiologic and psychosocial mechanisms of action and determining which pain conditions to investigate. Truly informative proof-of-concept and confirmatory randomized clinical trials will require careful selection of control groups, efforts to minimize bias from unblinding, and attention to the roles of patient mental set and treatment setting. Perspective: There is considerable promise for the use of psychedelic therapy for pain, but evidence-based recommendations for the design of future studies are needed to ensure that the results of this research are truly informative.
Article
The effects of psychedelic drugs in headache and chronic pain disorders have been reported for several decades, and now controlled studies are emerging. The existing evidence supports a lasting therapeutic benefit after limited dosing, a unique feature of the drug class that distinguishes it from conventional treatment. This commentary summarizes these reports of preventive effects of psychedelic drugs in headache and chronic pain disorders. The recently published controlled trial of psilocybin in migraine is reviewed, including its limitations. Several neurobiological targets of psychedelics that are related to headache and chronic pain are highlighted, though a clear separation of acute and lasting effects is key in uncovering the unique clinical effects of this drug class. Considerable investigation is required before the effects, safety, and mechanism of action of psychedelics in headache and chronic pain disorders can be known.
Article
There is a serious need for novel therapies that treat individuals with depression, including major depressive disorder (MDD) and treatment-resistant depression (TRD). An emerging body of research has demonstrated that psychedelic drugs such as psilocybin, combined with supportive psychotherapy, exert rapid and sustained antidepressant effects. The use of psychedelics is not new: they have a rich history with evidence of their use in ritual and medical settings. However, due to political, social, and cultural pressures, their use was limited until modern clinical trials began to emerge in the 2010s. This review provides a comprehensive look at the potential use of psilocybin in the treatment of depression and TRD. It includes an overview of the history, pharmacology, and proposed mechanism of psilocybin, and describes several published studies in the last decade which have provided evidence of the efficacy and safety of psilocybin-assisted psychotherapy for individuals with depression. It also includes a discussion of the limitations and barriers of current research on psychedelics. The results of these studies are contextualized within the current treatment landscape through an overview of the pathophysiology of depression and the treatments currently in use, as well as the clinical needs these novel therapies have the promise to fulfill.
Chapter
The serotonin (5-hydroxytryptamine, 5-HT) 2A receptor is most well known as the common target for classic psychedelic compounds. Interestingly, the 5-HT2A receptor is the most widely expressed mammalian serotonin receptor and is found in nearly every examined tissue type including neural, endocrine, endothelial, immune, and muscle, suggesting it could be a novel and pharmacological target for several types of disorders. Despite this, the bulk of research on the 5-HT2A receptor is focused on its role in the central nervous system (CNS). Recently, activation of 5-HT2A receptors has emerged as a new anti-inflammatory strategy. This review will describe recent findings regarding psychedelics as anti-inflammatory compounds, as well as parse out differences in functional selectivity and immune regulation that exist between a number of well-known hallucinogenic compounds.
Chapter
The therapeutic potential of psychedelics in headache and chronic pain disorders is documented over decades of anecdotal and early investigational reports, which have paved the way for the first controlled studies of psilocybin and lysergic acid diethylamide (LSD) in these disorders. The reported lasting clinical effects after limited dosing with psychedelics present a novel means for disease management, but considerable further study will be required to address disease-specific treatments, uncover mechanism(s) of action, and verify safety. In this chapter, these topics are reviewed with particular attention to the neurobiological systems that offer potential sources of psychedelics' unique clinical effects in headache and pain.
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Introdução: Doenças graves levantam questões existenciais que podem ser fonte de sofrimento psicológico e prejudicar o tratamento. Estudos com substâncias psicodélicas demonstram efeitos terapêuticos para ansiedade e depressão associadas a doenças físicas graves, principalmente câncer. Evidências indicam que a ayahuasca – uma bebida psicoativa de origem indígena preparada a partir das plantas Banisteriopsis caapi e Psychotria viridis, utilizada na medicina tradicional amazônica e em contextos ritualísticos/religiosos em diversos países – pode atuar como agente terapêutico no tratamento de transtornos psiquiátricos, destacando-se a depressão e a dependência de substâncias. Estudos preliminares sugerem também que a ayahuasca pode promover efeitos terapêuticos para doenças físicas. Objetivo: O presente estudo busca explorar como o uso ritual da ayahuasca durante o tratamento de doenças físicas graves influenciou o modo como as pessoas que vivenciaram essa experiência compreendem e se relacionam com a doença, procurando identificar os processos psicológicos envolvidos nos efeitos terapêuticos relatados. Métodos: Empregaram- se métodos de pesquisa qualitativa, em abordagem retrospectiva, exploratória e descritiva. Uma amostra intencional foi construída empregando-se critérios de intensidade e heterogeneidade, sendo que o fechamento foi determinado por saturação teórica. Quatorze participantes com diagnóstico atual ou anterior de doenças físicas graves e que fizeram uso ritual da ayahuasca durante o período do tratamento médico foram incluídos, envolvendo casos de câncer, HIV+ e doenças de natureza neurológica, reumatológica, gastrointestinal ou dermatológica. Os dados foram coletados por meio de entrevistas semiestruturadas de questões abertas em profundidade e o conteúdo foi analisado por análise temática, com temas emergentes. Resultados: Os temas identificados cobrem aspectos psicológicos, físicos e espirituais. Os participantes relataram que a experiência ritual com ayahuasca promoveu um espaço de introspecção e análise de conteúdos autobiográficos, com a ocorrência de catarses emocionais e a emersão de sentimentos positivos, o que contribuiu para a redução da ansiedade e de sintomas depressivos, favorecendo o bem-estar psicoemocional. Descreve-se também que a experiência facilitou a identificação de significados sobre a origem e o propósito da doença, bem como a sua ressignificação e aceitação, com reflexos positivos sobre a relação com a doença. Reflexões existenciais amplificadas pela experiência com ayahuasca parecem ter influenciado as concepções dos participantes sobre a vida e a morte, favorecendo a diminuição do medo da morte, maior apreciação da vida, mudanças em relações interpessoais e no estilo de vida. Os participantes relataram também que a experiência com ayahuasca promoveu um fortalecimento da espiritualidade, o que teria beneficiado o tratamento médico. No âmbito da saúde física, relatou-se que os efeitos psicofisiológicos da ayahuasca poderiam ter contribuído para a boa tolerabilidade do tratamento farmacológico, a estabilidade imunológica e a redução de dores crônicas – embora não tenham sido levantadas evidências clínicas comprobatórias. Conclusão: Os resultados deste estudo sugerem que o uso ritual da ayahuasca pode atuar como facilitador no processo de aceitação da doença, por meio de efeitos psicológicos que atuam sobre os significados atribuídos à doença, à vida e à morte, podendo favorecer um relacionamento mais equilibrado com a doença.
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Please see the significantly changed and expanded published article: https://www.researchgate.net/publication/362043763 * See also two other case studies: https://doi.org/10.13140/RG.2.2.20075.41764, and https://doi.org/10.13140/RG.2.2.24250.06089
Article
Hallucinogens, or psychedelics, are substances/drugs that have been used for over a millennium. The most well known are LSD, psilocybin, mescaline, and PCP. These substances may induce hallucinations as well as cause somatic and psychological symptoms. Because of the Controlled Substances Act of 1970, there has been very little research done to determine the long-term consequences or perhaps potential benefit of misuse and abuse of hallucinogens. Typically, these drugs are not abused but more often misused. Recently, there has been a renewed interest in these compounds, which may lead to possible therapeutic options.
Article
Psychedelics are increasingly being recognized for their potential to treat a wide range of brain disorders including depression, post-traumatic stress disorder (PTSD), and substance use disorder. Their broad therapeutic potential might result from an ability to rescue cortical atrophy common to many neuropsychiatric and neurodegenerative diseases by impacting neurotrophic factor gene expression, activating neuronal growth and survival mechanisms, and modulating the immune system. While the therapeutic potential of psychedelics has not yet been extended to neurodegenerative disorders, we provide evidence suggesting that approaches based on psychedelic science might prove useful for treating these diseases. The primary target of psychedelics, the 5-HT2A receptor, plays key roles in cortical neuron health and is dysregulated in Alzheimer’s disease. Moreover, evidence suggests that psychedelics and related compounds could prove useful for treating the behavioral and psychological symptoms of dementia (BPSD). While more research is needed to probe the effects of psychedelics in models of neurodegenerative diseases, the robust effects of these compounds on structural and functional neuroplasticity and inflammation clearly warrant further investigation.
Article
Background Suicide is one of the leading causes of death worldwide and rates within the United States have risen over the past two decades. Hence, there is a critical need for novel tools to treat suicidal ideation and related mental health conditions. 3,4-Methylenedioxymethamphetamine (MDMA)/ecstasy and classic psychedelics may be two such tools. Aims The aim of this study was to assess non-causal associations between MDMA/ecstasy and classic psychedelic use and psychological distress and suicide risk. Methods In this study, we examined the aforementioned associations among 484,732 adult participants in the National Survey on Drug Use and Health (2008–2019). Results Lifetime MDMA/ecstasy use was associated with reduced odds of past year suicidal thinking (10% reduced odds; odds ratio (OR) = 0.90; 95% confidence interval, CI = (0.84–0.97); p < 0.01) and past year suicidal planning (OR = 0.88; 95% CI = (0.78–0.99); p < 0.05). Furthermore, lifetime psilocybin use was associated with reduced odds of past month psychological distress (OR = 0.78; 95% CI = (0.73–0.84); p < 0.001) and past year suicidal thinking (OR = 0.90; 95% CI = (0.83–0.96); p < 0.01). Finally, lysergic acid diethylamide (LSD) was associated with increased odds of past year suicidal thinking (OR = 1.07; 95% CI = (1.00–1.15); p < 0.05). Conclusion MDMA/ecstasy and psilocybin use are associated with reduced odds of suicidal thinking and related outcomes—though experimental studies are needed to determine whether these associations are causal. These findings call for more research into the efficacy of MDMA/ecstasy and classic psychedelics for treating psychological distress and suicidal thoughts and behaviors, and for updated drug legislation that allows for further investigation into these substances.
Article
Basic pain research has shed light on key cellular and molecular mechanisms underlying nociceptive and phenomenological aspects of pain. Despite these advances, [[we still yearn for] the discovery of novel therapeutic strategies to address the unmet needs of about 70% of chronic neuropathic pain patients whose pain fails to respond to opioids as well as to other conventional analgesic agents. Importantly, a substantial body of clinical observations over the past decade cumulatively suggests that the psychedelic class of drugs may possess heuristic value for understanding and treating chronic pain conditions. The present review presents a theoretical framework for hitherto insufficiently understood neuroscience-based mechanisms of psychedelics’ potential analgesic effects. To that end, searches of PubMed-indexed journals were performed using the following Medical Subject Headings' terms: pain, analgesia, inflammatory, brain connectivity, ketamine, psilocybin, functional imaging, and dendrites. Recursive sets of scientific and clinical evidence extracted from this literature review were summarized within the following key areas: (1) studies employing psychedelics for alleviation of physical and emotional pain; (2) potential neuro-restorative effects of psychedelics to remediate the impaired connectivity underlying the dissociation between pain-related conscious states/cognitions and the subcortical activity/function leading to the eventual chronicity through immediate and long-term effects on dentritic plasticity; (3) anti-neuroinflammatory and pro-immunomodulatory actions of psychedelics as the may pertain to the role of these factors in the pathogenesis of neuropathic pain; (4) safety, legal, and ethical consideration inherent in psychedelics’ pharmacotherapy. In addition to direct beneficial effects in terms of reduction of pain and suffering, psychedelics’ inclusion in the analgesic armamentarium will contribute to deeper and more sophisticated insights not only into pain syndromes but also into frequently comorbid psychiatric condition associated with emotional pain, e.g., depressive and anxiety disorders. Further inquiry is clearly warranted into the above areas that have potential to evolve into further elucidate the mechanisms of chronic pain and affective disorders, and lead to the development of innovative, safe, and more efficacious neurobiologically-based therapeutic approaches.
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Rationale: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. Objectives: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. Methods: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. Results: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. Conclusions: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
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Neuroinflammation is recognised as one of the potential mechanisms mediating the onset of a broad range of psychiatric disorders and may contribute to nonresponsiveness to current therapies. Both preclinical and clinical studies have indicated that aberrant inflammatory responses can result in altered behavioral responses and cognitive deficits. In this review, we discuss the role of inflammation in the pathogenesis of neuropsychiatric disorders and ask the question if certain genetic copy-number variants (CNVs) associated with psychiatric disorders might play a role in modulating inflammation. Furthermore, we detail some of the potential treatment strategies for psychiatric disorders that may operate by altering inflammatory responses.
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Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.
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Serotonin [5-hydroxytryptamine (5-HT)] plays an important role in many organs as a peripheral hormone. Most of the body’s serotonin is circulating in the bloodstream, transported by blood platelets and is released upon activation. The functions of serotonin are mediated by members of the 7 known mammalian serotonin receptor subtype classes (15 known subtypes), the serotonin transporter (SERT), and by covalent binding of serotonin to different effector proteins. Almost all immune cells express at least one serotonin component. In recent years, a number of immunoregulatory functions have been ascribed to serotonin. In monocytes/macrophages, for example, serotonin modulates cytokine secretion. Serotonin can also suppress the release of tumor necrosis factor-α and interleukin-1β by activating serotonin receptors. Furthermore, neutrophil recruitment and T-cell activation can both be mediated by serotonin. These are only a few of the known immunomodulatory roles of serotonin that we will review here.
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Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.
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Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes. Trial Registration ClinicalTrials.gov identifier: NCT00465595
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Background: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. Trial registration: ClinicalTrials.gov Identifier: NCT00957359.
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Objective and designTo investigate the therapeutic effects of various HDAC inhibitors on the development of chronic allergic airway disease in mice with airway inflammation, airway remodeling, and airway hyperresponsiveness. SubjectsWild-type BALB/C mice (N = 72). TreatmentTubastatin A HCl [TSA, a selective histone deacetylase 6 (HDAC6) inhibitor], PCI-34051 (a selective HDAC8 inhibitor), and givinostat (a broad-spectrum HDAC inhibitor that inhibits class I and class II HDACs and several pro-inflammatory cytokines). Methods Mice were divided into six groups: control, asthma, dexamethasone (positive control), TSA, PCI-34051, and givinostat (n = 12 per group). Twenty-four hours after OVA nebulization, airway hyperresponsiveness, inflammation, and remodeling were assessed. ResultsThe chronic asthma mouse model produced typical airway inflammation, airway remodeling, and airway hyperresponsiveness. Administration of PCI-34051 and dexamethasone reduced the eosinophilic inflammation and airway hyperresponsiveness in asthma to reduce the airway remodeling. Treatment with Tubastatin A HCl reduced airway inflammation and was associated with decreased IL-4, IL-5 and total inflammatory cell count, as well as goblet cell metaplasia and subepithelial fibrosis; however, this outcome was not as effective as that with dexamethasone. TGF-β1 expression in the cytoplasm of airway epithelium of mice in the Tubastatin A HCl group was reduced and expression of α-SMA in the airway smooth muscle was also decreased. Conclusions The results suggested that treatment with HDAC inhibitors can reduce airway inflammation, airway remodeling, and airway hyperresponsiveness in chronic allergic airway disease in mice.
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Background: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. Methods: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. Findings: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. Interpretation: This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. Funding: Medical Research Council.
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Brain diseases and disorders such as Alzheimer disease, Parkinson disease, depression, schizophrenia, autism, and addiction lead to reduced quality of daily life through abnormal thoughts, perceptions, emotional states, and behavior. While the underlying mechanisms remain poorly understood, human and animal studies have supported a role of neuroinflammation in the etiology of these diseases. In the central nervous system, an increased inflammatory response is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. In turn, the pro-inflammatory cytokines aggravate and propagate neuroinflammation, degenerating healthy neurons and impairing brain functions. Therefore, activated microglia may play a key role in neuroinflammatory processes contributing to the pathogenesis of psychiatric disorders and neurodegeneration.
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Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of "ego-dissolution" and "altered meaning," implying the importance of this particular circuit for the maintenance of "self" or "ego" and its processing of "meaning." Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.
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Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybinassisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network. © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
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The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the beta(2)-adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal (e.g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate (mechanisms that translate conformation changes into differential signaling), and distal mechanisms (differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts.
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The depressive state has been characterised as one of elevated inflammation, which holds promise for better understanding treatment-resistance in affective disorders as well as for future developments in treatment stratification. Aiming to investigate alterations in the inflammatory profiles of individuals with depression as putative biomarkers for clinical response, we conducted a meta-analyses examining data from 35 studies that investigated inflammation before and after treatment in depressed patients together with a measure of clinical response. There were sufficient data to analyse IL-6, TNFα and CRP. Levels of IL-6 decreased with antidepressant treatment regardless of outcome, whereas persistently elevated TNFα was associated with prospectively determined treatment resistance. Treatment non-responders tended to have higher baseline inflammation, using a composite measure of inflammatory markers. Our findings suggest that elevated levels of inflammation are contributory to treatment resistance. Combining inflammatory biomarkers might prove a useful tool to improve diagnosis and detection of treatment refractoriness, and targeting persistent inflammation in treatment-resistant depression may offer a potential target for the development of novel intervention strategies. Copyright © 2015. Published by Elsevier B.V.
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Serotonin receptors (5-HTRs) mediate both central and peripheral control on numerous physiological functions such as sleep/wake cycle, thermoregulation, food intake, nociception, locomotion, sexual behavior, gastrointestinal motility, blood coagulation, and cardiovascular homeostasis. Six families of the G-protein-coupled receptors comprise most of serotonin receptors besides the conserved 5-HT3R Cys-loop type which belongs to the family of Cys-loop ligand-gated cation channel receptors. Many of these receptors are targets of pharmaceutical drugs, justifying the importance for elucidating their coupling, signaling and functioning. Recently, special interest has been focused on their trafficking inside cell lines or neurons in conjunction with their interaction with partner proteins. In this review, we describe the trafficking of 5-HTRs including their internalization, desensitization, or addressing to the plasma membrane depending on specific mechanisms which are peculiar for each class of serotonin receptor. © 2015 Elsevier Inc. All rights reserved.
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Serotonin or 5- hydoxytryptamine (5-HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS), and in the respective organ systems. Peripheral 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5-HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5-HT signalling have been described in inflammatory conditions of the gut, such inflammatory bowel disease. The association between 5-HT and inflammation, however, is not limited to the gut; as changes in 5-HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as “5-HT,” “EC cell,” “immune cells,” and “inflammation” in pubmed. gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5-HT in biological functions with a particular focus on immune activation and inflammation.This article is protected by copyright. All rights reserved.
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Serotonin receptors are G-protein-coupled receptors (GPCRs) involved in a variety of psychiatric disorders. G-proteins, heterotrimeric complexes that couple to multiple receptors, are activated when their receptor is bound by the appropriate ligand. Activation triggers a cascade of further signalling events that ultimately result in cell function changes. Each of the several known G-protein types can activate multiple pathways. Interestingly, since several G-proteins can couple to the same serotonin receptor type, receptor activation can result in induction of different pathways. To reach a better understanding of the role, interactions and expression of G-proteins a literature search was performed in order to list all the known heterotrimeric combinations and serotonin receptor complexes. Public databases were analysed to collect transcript and protein expression data relating to G-proteins in neural tissues. Only a very small number of heterotrimeric combinations and G-protein-receptor complexes out of the possible thousands suggested by expression data analysis have been examined experimentally. In addition this has mostly been obtained using insect, hamster, rat and, to a lesser extent, human cell lines. Besides highlighting which interactions have not been explored, our findings suggest additional possible interactions that should be examined based on our expression data analysis.
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Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). The pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.
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Association of the neurotransmitter serotonin (5-HT) with the pathogenesis of allergic asthma is well recognized and its role as a chemoattractant for eosinophils (Eos) in vitro and in vivo has been previously demonstrated. Here we have examined the regulation of 5-HT-induced human and murine Eos trafficking and migration at a cellular and molecular level. Eos from allergic donors and bone marrow-derived murine Eos (BM-Eos) were found to predominantly express the 5-HT2A receptor. Exposure to 5-HT or 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-HT2A/C selective agonist, induced rolling of human Eos and AML14.3D10 human Eos-like cells on vascular cell adhesion molecule (VCAM)-1 under conditions of flow in vitro coupled with distinct cytoskeletal and cell shape changes as well as phosphorylation of MAPK. Blockade of 5-HT2A or of ROCK MAPK, PI3K, PKC and calmodulin, but not G(αi)-proteins, with specific inhibitors inhibited DOI-induced rolling, actin polymerization and changes in morphology of VCAM-1-adherent AML14.3D10 cells. More extensive studies with murine BM-Eos demonstrated the role of 5-HT in promoting rolling in vivo within inflamed post-capillary venules of the mouse cremaster microcirculation and confirmed that down-stream signaling of 5-HT2A activation involves ROCK, MAPK, PI3K, PKC and calmodulin similar to AML14.3D10 cells. DOI-induced migration of BM-Eos is also dependent on these signaling molecules and requires Ca(2+). Further, activation of 5-HT2A with DOI led to an increase in intracellular Ca(2+) levels in murine BM-Eos. Overall, these data demonstrate that 5-HT (or DOI)/5-HT2A interaction regulates Eos trafficking and migration by promoting actin polymerization associated with changes in cell shape/morphology that favor cellular trafficking and recruitment via activation of specific intracellular signaling molecules (ROCK, MAPK, PI3K and the PKC-calmodulin pathway).
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Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
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Objective: To explore the inflammatory processes in the pathogenesis of psychiatric symptoms and the prognostic value of psychiatric comorbidities in multiple sclerosis (MS). Methods: Four hundred five patients with relapsing-remitting (RR) MS underwent psychiatric evaluation by means of Beck Depression Inventory II (BDI-II) and State/Trait Anxiety Inventory (STAI-Y). The inflammatory activity level was assessed by MRI. In a subset of 111 treatment-naive patients, CSF levels of proinflammatory cytokines were determined. Correlation and regression analyses were performed to determine associations between variables. Results: Relapsing patients demonstrated greater values of STAI-state and BDI-II compared with remitting patients but comparable trait-anxiety scores. There were no significant differences in psychometric parameters between relapsing and asymptomatic MRI-active patients, highlighting the effect of subclinical inflammation on mood disturbances. A significant reduction of STAI-state and BDI-II scores was recorded, along with the subsiding of neuroinflammation. Interleukin-2 CSF levels were found to correlate with STAI-state, while tumor necrosis factor-α and interleukin-1β correlated with BDI-II. Because emotional disorders were associated with subclinical inflammation, variations of the psychometric profile were able to detect subclinical reactivation earlier. In line with this, high STAI-state values considerably predicted the possibility of disease reactivation. Conclusions: Mood alterations are induced by intrathecal inflammation, even though not clinically apparent, and are able to predict inflammatory reactivations in RRMS. Inflammation is therefore a biological event, not less important than the traditional psychosocial factors, involved in mood disorders.
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G protein-coupled receptors (GPCRs), which are modulated by a variety of endogenous and synthetic ligands, represent the largest family of druggable targets in the human genome. Recent structural and molecular studies have both transformed and expanded classical concepts of receptor pharmacology and have begun to illuminate the distinct mechanisms by which structurally, chemically, and functionally diverse ligands modulate GPCR function. These molecular insights into ligand engagement and action have enabled new computational methods and accelerated the discovery of novel ligands and tool compounds, especially for understudied and orphan GPCRs. These advances promise to streamline the development of GPCR-targeted medications.
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Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing anti-inflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network “resetting” after acute effects have resolved. Anti-inflammatory effects may hold promise for efficacy in treatment of inflammation-related non-psychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched. This article is protected by copyright. All rights reserved.
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Uveal melanomas are molecularly distinct from cutaneous melanomas and lack mutations in BRAF, NRAS, KIT, and NF1. Instead, they are characterized by activating mutations in GNAQ and GNA11, two highly homologous α subunits of Gαq/11 heterotrimeric G proteins, and in PLCB4 (phospholipase C β4), the downstream effector of Gαq signaling. We analyzed genomics data from 136 uveal melanoma samples and found a recurrent mutation in CYSLTR2 (cysteinyl leukotriene receptor 2) encoding a p.Leu129Gln substitution in 4 of 9 samples that lacked mutations in GNAQ, GNA11, and PLCB4 but in 0 of 127 samples that harbored mutations in these genes. The Leu129Gln CysLT2R mutant protein constitutively activates endogenous Gαq and is unresponsive to stimulation by leukotriene. Expression of Leu129Gln CysLT2R in melanocytes enforces expression of a melanocyte-lineage signature, drives phorbol ester-independent growth in vitro, and promotes tumorigenesis in vivo. Our findings implicate CYSLTR2 as a uveal melanoma oncogene and highlight the critical role of Gαq signaling in uveal melanoma pathogenesis.